Antifungal agents may be administered in a variety of dosage forms such as creams or ointment, tablets, capsules and suppositories. For example, tablets, suppositories and capsules containing one or more antifungal agents are widely used intravaginally for.the treatment of vaginal candidiasis. Retention of the tablet, capsule or suppository in the vagina and stability of the medicinal agent, during and after manufacture, are of primary importance in the success of such treatment.
Nystatin, for example, has a high degree of sensitivity to heat, oxygen, moisture and extremes in pH. This is due to the highly unsaturated nature of the nystatin molecule. Inactivation of amorphous nystatin occurs even at room temperature and below when subjected to an oxygen source. Elevated moisture conditions and elevated temperatures compound the degradation process. Further, it is believed that once oxidation begins it cannot be stopped, even by storage at -20.degree. C.
Solid nystatin intravaginal tablets typically comprise the medicament, solid binders and about 6 percent by weight of water. The water content, as well as elevated temperatures used during the fabrication of such tablets, can significantly reduce the activity of the drug. Further, premature expulsion of the hard tablet from the vaginal tract can occur.
Jackson et al. U.S. Pat. No. 4,542,020 discloses long-lasting adhesive antifungal suppositories comprising an antifungal agent, e.g. nystatin, together with a hydrocolloid and a low melting suppository base. These suppositories melt at body temperature, releasing the drug-containing hydrooolloid which adheres to the vaginal membrane to provide a uniform distribution of the drug at the site of.the infection. However, the water soluble or hydratable nature of the hydrocolloid can adversely affect the drug's shelf life by allowing and/or contributing to oxidative degradation.
Riley Jr., et al. U.S. Pat. No. 4,551,148, discloses a sustained release vaginal delivery system providing a more uniform release of the medicament over an extended period. In this system, a non-lipoidal internal phase containing the antifungal agent is suspended within the lipoidal external phase. The internal phase actually comprises small drug-containing packets which are diffused throughout the external phase. The external phase in turn provides adhesion to the vaginal membrane at the site of infection. The internal phase disclosed for nystatin, however, contains 60 percent by weight of water, which again can significantly degrade the activity of the nystatin over time.
Leigh et al. U.S. Pat. No. 4,291,062, discloses pharmaceutical compositions for the skin, containing urea, designed to provide good stability and a smooth texture. These compositions comprise a medicament, e.g. nystatin, presented as small particles coated with a wax; an inclusion compound of urea with a straight-chain aliphatic compound; an inert soluble powder; and an inert carrier into which the aforementioned components are suspended. During the formation of these skin treatment compositions, however, the medicament is subjected to a complex process which includes exposure to temperatures of 60.degree. C. and above during the wax-coating procedure.
An antifungal capsule formulation, for use in oral or vaginal capsules, providing enhanced stability for moisture or oxygen sensitive antifungal agents and, in the case of the vaginal capsule formulation, good adhesion to the vaginal membrane. A method for fabricating such capsules would be useful additions to the art.